Homeobox genes occupy key positions in the regulatory gene hierarchy responsible for establishing the embryonic body plan in Drosophila, and are thought to play analogous roles in the development of higher vertebrates. The homeobox gene Rpx (for Rathke's pouch homeobox) is expressed during gastrulation in the prospective anterior neural plate, and at later stages in Rathke's pouch, the primordium of the anterior and intermediate lobes of the pituitary. Expression in Rathke's pouch is extinguished between 13.5 and 14.5 days of embryogenesis, coincident with the differentiation of pituitary-specific cell types. Using lacZ reporter genes, it has been found that proper spatial and temporal expression in the anterior neural plate can be recapitulated in transgenic mice by as little as 600 bp of upstream sequence and the first intron. Additional elements are required for expression in Rathke's pouch. In addition, an element has been uncovered that directs transgene expression to a region of the hypothalamus and incipient posterior lobe that is in direct contact with Rathke's pouch. In vitro tissue recombination experiments have established that this expression is "induced" by contact with the pouch. It is proposed that this element may be present in other genes that normally respond to signals emanating from the pouch during the determination of the hypothalamic-pituitary axis. The role Rpx plays in pituitary development has been investigated in gain-of-function mouse models. Persistent expression in the pituitary has been achieved by directing expression of Rpx in transgenic mice with pituitary-specific promoters. Transgenic mice bearing alpha-glycoprotein subunit promoter-Rpx fusion genes express Rpx in the pituitary after the endogenous gene normally turns off. These mice are dwarfed and have underdeveloped reproductive tracts. Their pituitaries are very small and are deficient in gonadotroph, thyrotroph, lactotroph, and somatotroph cell lineages. These results indicate that the Rpx gene product must be downregulated during development for proper differentiation of the pituitary. The phenotype of these mice is similar to existing dwarf mutants suggesting that Rpx mis-expression may be causatively involved in the genesis of certain types of pituitary dysfunction in mouse and man.